TNF-α Converting Enzyme (TACE) (also known as A Disintegrin And Metalloprotease 17 (ADAM17)), is a membrane-bound metalloprotease responsible for cleaving a variety of pathologically significant substrates. Initially identified as the enzyme responsible for solubilising membrane-associated pro-TNF-α, a process subsequently termed “ectodomain shedding”, TACE has since proved capable of cleaving a wide range of substrates, such as epidermal growth factor receptor (EGFR) ligands, extracellular Notch, cell-surface receptors and adhesion molecules. As proteolytic cleavage is an indispensable activation event for many of these substrates, TACE has emerged as an attractive therapeutic target for the treatment of cancer and rheumatoid arthritis. The role of TACE is reviewed in Murphy (Nature Reviews: Cancer, 8(12): 929-941, 2008).
A role for TACE in regulating TNF-α and hence the potential utility of inhibiting TACE as a therapeutic strategy for treating inflammatory disease has been recognised for some time and many companies have tried to develop small molecule inhibitors of TACE. However, the metalloprotease family are highly conserved and developing selective small molecule inhibitors has proven to be a significant challenge. Early trials using broader spectrum metalloprotease inhibitors were prone to toxicity issues and as such the ability to generate selective inhibitors of this family is desirable, see Moss et al (Nature Clinical Practice, 4(6): 300-309, 2008).
An alternative strategy to developing a selective TACE inhibitor would be to utilise the selectivity that is generally achievable with antibodies. However, while antibodies which bind to TACE have been reported and are commercially available, unusually none of these to date have had antagonistic activity. By way of example of this, while WO 96/041624 discloses the identification of TACE enzyme and suggests producing anti-TACE antibodies, no antibodies are disclosed in the application, still less antibodies having specific functional properties such as antagonist antibodies. This in turn means that the development of antibody based therapeutics capable of blocking TACE activity remains an unsolved problem in the art.